Factor H
Encyclopedia
Factor H is a member of the regulators of complement activation family and is a complement control protein
. It is a large (155 kilodaltons), soluble glycoprotein
that circulates in human plasma
(at a concentration of 500–800 micrograms per milliliter). Its principal function is to regulate the Alternative Pathway of the complement system
, ensuring that the complement system is directed towards pathogens and does not damage host tissue. Factor H regulates complement activation on self cells by possessing both cofactor activity for the Factor I mediated C3b
cleavage, and decay accelerating activity against the alternative pathway C3 convertase, C3bBb. Factor H protects self cells from complement activation but not bacteria
/viruses, in that it binds to glycosaminoglycans (GAGs) that are present on host cells but not pathogen cell surfaces.
(CCP) modules (also referred to as Short Consensus Repeats or sushi domains) arranged head to tail. Each of the CCP modules consists of around 60 amino acid
s with four cysteine
residues disulfide bond
ed in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant tryptophan
residue. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCPs 12-13, CCP 15, CCP 16, CCPs 15-16, and CCPs 19-20. The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate and CCPs 1-4 in complex with C3b have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution. Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or 19-20.
.
indicating a causal relationship between the SNP and disease. Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.
; B. duttonii; B. recurrentis; Candida albicans
; Francisella tularensis
; Haemophilus influenzae
; Neisseria meningitidis
; and Streptococcus pyogenes
.
with Complement component 3.
and coworkers in the moss bioreactor
, in a process called molecular farming
.
Complement control protein
The complement system distinguishes "self" from "non-self" via a range of specialized cell-surface and soluble proteins. These homologous proteins belong to a family called the "regulators of complement activation " or "complement control proteins "...
. It is a large (155 kilodaltons), soluble glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that circulates in human plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
(at a concentration of 500–800 micrograms per milliliter). Its principal function is to regulate the Alternative Pathway of the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, ensuring that the complement system is directed towards pathogens and does not damage host tissue. Factor H regulates complement activation on self cells by possessing both cofactor activity for the Factor I mediated C3b
C3b
C3b is the larger of two elements formed by the cleavage of complement component 3. C3b covalently bonds to microbial cell surfaces within an organism's body. This leads to the production of surface-bound C3 convertase and thus more C3b components. Bound C3b also aids in opsonization of the microbe...
cleavage, and decay accelerating activity against the alternative pathway C3 convertase, C3bBb. Factor H protects self cells from complement activation but not bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
/viruses, in that it binds to glycosaminoglycans (GAGs) that are present on host cells but not pathogen cell surfaces.
Structure
The molecule is made up of 20 complement control proteinComplement control protein
The complement system distinguishes "self" from "non-self" via a range of specialized cell-surface and soluble proteins. These homologous proteins belong to a family called the "regulators of complement activation " or "complement control proteins "...
(CCP) modules (also referred to as Short Consensus Repeats or sushi domains) arranged head to tail. Each of the CCP modules consists of around 60 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s with four cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
ed in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
residue. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCPs 12-13, CCP 15, CCP 16, CCPs 15-16, and CCPs 19-20. The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate and CCPs 1-4 in complex with C3b have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution. Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or 19-20.
Clinical significance
Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arrising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms (SNPs) in factor H often result in pathologies. Moreover the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulenceVirulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
.
Age-related macular degeneration
Recently it was discovered that about 35% of individuals carry an at-risk SNP in one or both copies of their factor H gene. Homozygous individuals have an approximately sevenfold increased chance of developing age-related macular degeneration, while heterozygotes have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and heparinHeparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
indicating a causal relationship between the SNP and disease. Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.
Atypical haemolytic uraemic syndrome
Haemolytic uraemic syndrome (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, factor I and membrane cofactor protein), with the factor H mutations being the most numerous. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self and have been shown to disrupt heparin and C3d binding.Recruitment by pathogens
Given the central role of factor H in protecting cells from complement, it is not surprising that several important human pathogens have evolved mechanisms for recruiting factor H. This recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence. Pathogens that have been shown to recruit factor H include: Aspergillus spp.; Borrelia burgdorferiBorrelia burgdorferi
Borrelia burgdorferi is a species of Gram negative bacteria of the spirochete class of the genus Borrelia. B. burgdorferi is predominant in North America, but also exists in Europe, and is the agent of Lyme disease....
; B. duttonii; B. recurrentis; Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
; Francisella tularensis
Francisella tularensis
Francisella tularensis is a pathogenic species of gram-negative bacteria and the causative agent of tularemia or rabbit fever. It is a facultative intracellular bacterium....
; Haemophilus influenzae
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
; Neisseria meningitidis
Neisseria meningitidis
Neisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...
; and Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
.
Interactions
Factor H has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Complement component 3.
Recombinant production
Biologically active Factor H has been produced by Ralf ReskiRalf Reski
Ralf Reski is a German Professor of Plant Biotechnology and former Dean of the Faculty of Biology of the University of Freiburg...
and coworkers in the moss bioreactor
Moss bioreactor
thumb|350px|Moss bioreactor with [[Physcomitrella patens]]A moss bioreactor is a photobioreactor used for the cultivation and propagation of mosses...
, in a process called molecular farming
Molecular farming
Molecular farming is the use of genetically engineered crops to produce compounds with therapeutic value. These crops will become biological factories used to generate drugs and other difficult or expensive products...
.